MTRFR

protein-coding

mitochondrial translation release factor in rescue, the group of Mitochondrial translation release factor family

Gene summary

This nuclear gene encodes a mitochondrial matrix protein that appears to contribute to peptide chain termination in the mitochondrial translation machinery. Two different 1 bp deletions (resulting in the same premature stop codon)result in decreased mitochondrial translation, decreased levels of oxidative phosphorylation complexes and encepthalomyopathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2010]

Previous symbols:

C12orf65

MANE transcript

NM_152269.5

Inheritance

ClinVar variants

P:24U:60B:38

Top phenotype

Combined oxidative phosphorylation deficiency 7; Spastic paraplegia 55, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.29

Max pathogenic AF

—

Genomic locus

chr12:123,233,385-123,258,079

External References & Databases

Ensembl (ENSG00000130921)

Transcript & Mutation Effects

hg38 • Region Span ~24.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Leigh syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between C12orf65 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of December 9, 2019. The C12orf65 gene encodes an important mitochondrial translation release factor that functions in releasing newly synthesized peptides from the mitochondrial ribosome. The C12orf65 gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2010 (PMID: 20598281). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included four unique variants identified in six cases from five publications (PMIDs: 20598281, 24284555, 27858754, 25995486, 26380172). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by known biochemical function, expression, functional alteration in patient cells, functional alteration in non-patient cells, and rescue in patient cells (PMIDs: 27977873, 18853439, 20598281, 22821833, 27858754, 26380172). In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed from the first proposal of the association. This classification was approved by NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on December 9, 2019 (SOP Version 7).

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *MTRFR* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of May 23, 2024. The *MTRFR* gene (previously known as *C12ORF65*) encodes an important mitochondrial translation release factor that functions in releasing newly synthesized peptides from the mitochondrial ribosome. *MTRFR* was first reported in relation to autosomal recessive mitochondrial disease in 2010 (PMID: 20598281). While various names have been given to the constellation of features seen in those with *MTRFR*-related disorders, including combined oxidative phosphorylation deficiency, spastic paraplegia, and Charcot Marie Tooth disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the MTRFR phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, *MTRFR* was first curated by this Expert Panel for its association with Leigh syndrome spectrum (LSS) on December 9, 2019 (SOP V7), with a final classification of Definitive. This current curation for the association with primary mitochondrial disease includes the six cases included in the LSS curation. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included five variants (all frameshift or termination) in eight probands from seven publications (PMIDs: 20598281, 24284555, 25995486, 24198383, 26380172, 23188110, 27858754). Clinical features in affected individuals include LSS, psychomotor regression, intellectual disability, muscle atrophy, myopathy, ataxia, spastic paraplegia, hypotonia, dysarthria, axonal polyneuropathy, optic atrophy, ophthalmoplegia, ptosis, nystagmus, strabismus, respiratory insufficiency, swallowing difficulty, and failure to thrive. Age of onset varies from childhood to adulthood. Outcomes are also quite variable as there have been reports of death in childhood as well as affected individuals living well into adulthood with a very slowly progressive disease course. Muscle biopsies show decreased activities of complexes I, II + III, and IV and COX negative fibers. Elevated lactate, decreased activities of complexes I, IV, and V in fibroblasts and decreased synthesis of mitochondrial proteins in patient fibroblasts has also been reported. The mechanism of disease is loss of function. This gene-disease association is also supported by the known biochemical function of MTRFR in mitochondrial translation, functional alteration in patient and non-patient cells, and rescue in patient cells (PMIDs: 20598281, 27858754, 26380172, 22821833). In summary, there is definitive evidence to support the relationship between *MTRFR* and primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on May 23, 2024 (SOP Version 10).

Leigh syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: Illumina

combined oxidative phosphorylation defect type 7DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013306

Submitter: G2P

combined oxidative phosphorylation defect type 7STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013306

Submitter: Labcorp Genetics (formerly Invitae)

combined oxidative phosphorylation defect type 7MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013306

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Combined oxidative phosphorylation deficiency 7; Spastic paraplegia 55, autosomal recessiveAR

Manifestation: Biochemical; Neurologic; Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 3479531; 20598281; 23188110; 24198383

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MTRFR variants in ClinVar

15 Conditions Cataloged

Combined oxidative phosphorylation defect type 7Total: 108

Spastic paraplegiaTotal: 101

not providedTotal: 40

MTRFR-related disorderTotal: 12

Hereditary spastic paraplegia 55Total: 11

not specifiedTotal: 11

Hereditary spastic paraplegiaTotal: 10

C12ORF65 & MTRFR-related disordersTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_152269.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				35 clinvar		35
missense		1 clinvar	57 clinvar	3 clinvar		61
nonsense	2 clinvar	2 clinvar				4
start loss						0
frameshift	9 clinvar	7 clinvar	3 clinvar			19
splice donor/acceptor (+/-2bp)	2 clinvar	1 clinvar				3
Total	13	11	60	38	0	122

Highest pathogenic variant AF is 0.00021744652

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 39 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_152269.5	RefSeq	NP_689482.1	2	MANE Select
ENST00000253233.6	Ensembl	ENSP00000253233.1	2	MANE Select
NM_001143905.2	RefSeq	NP_001137377.1	2	Standard
NM_001194995.1	RefSeq	NP_001181924.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

translational termination

Molecular Function

translation release factor activity

Cellular Component

mitochondrion
mitochondrial large ribosomal subunit

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000253233
Coding exons: 2
Length: 25044
Individuals with no LoFs: 125657
Homozygous LoFs: 0
Heterozygous LoFs: 91
Defined: 125748
p: 0.000362

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.433	102	90.4	1.13	0.00000531	1063
Missense (PolyPhen)		28	30.652	0.91349		355
Synonymous	1.13	30	38.9	0.770	0.00000256	330
Loss of Function	1.74	2	6.94	0.288	4.80e-7	69

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.0011	0.0011	notable
European (Non-Finnish)	0.00054	0.00054	rare
South Asian	0.000098	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May act as a codon-independent translation release factor that has lost all stop codon specificity and directs the termination of translation in mitochondrion. May help rescuing stalled mitoribosomes during translation (By similarity). {ECO:0000250}.;
Disease: DISEASE: Combined oxidative phosphorylation deficiency 7 (COXPD7) [MIM:613559]: A mitochondrial disease resulting in encephalomyopathy. Clinical manifestations include psychomotor delay and regression, ataxia, optic atrophy, nystagmus and muscle atrophy and weakness. {ECO:0000269|PubMed:20598281}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Spastic paraplegia 55, autosomal recessive (SPG55) [MIM:615035]: A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. Complicated forms are recognized by additional variable features including spastic quadriparesis, seizures, dementia, amyotrophy, extrapyramidal disturbance, cerebral or cerebellar atrophy, optic atrophy, and peripheral neuropathy, as well as by extra neurological manifestations. {ECO:0000269|PubMed:23188110}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0748

Intolerance Scores

LoFtool: 0.863
RVIS EVS: 0.13
RVIS percentile EVS: 63

Essentials

Essential (CRISPR): N
Essential (CRISPR2): E
Essential (gene trap): H

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium